Evidence regarding a functional serotonin (5-hydroxytryptamine) signaling system in bone has generated considerable recent interest. The specific biochemical nature of serotoninergic pathways and their direct and/or indirect effects on bone metabolism are still unclear. Clinical evidence supports an effect of serotonin and altered serotonin signaling on bone metabolism. Serotonin is involved in the pathophysiology of depression, and therefore studies of depression and antidepressant treatments (as modulators of the serotonin system) are relevant with regard to bone outcomes. Studies on the effect of depression on bone mineral density (BMD) and fractures have been mixed. Studies on the associations between antidepressant use and BMD and/or fractures are more consistent. SSRIs have been associated with lower BMD and increased rates of bone loss, as well as increased rates of fracture after accounting for falls. These studies are limited by confounding because depression is potentially associated with both the outcome of interest (BMD and fracture) and the exposure (SSRIs). With mounting evidence for an effect on bone, this review considers the question of causality and whether selective serotonin reuptake inhibitors should be considered among those medications that contribute to bone loss, and therefore prompt clinicians to evaluate BMD proactively. Future research will be required to confirm the serotoninergic effects on bone and the biochemical pathways involved, and to identify clinical implications for treatment based on this novel pathway.